Interindividual Variability: Regulatory Considerations

Transcription

1 Interindividual Variability: Regulatory Considerations John Vandenberg Human Health Risk Assessment National Program Director Division Director National Center for Environmental Assessment (NCEA) Office of Research and Development (ORD) U.S. Environmental Protection Agency Disclaimer: The views expressed are those of the authors and do not necessarily reflect the views or policies of the U.S. EPA. Office of Research and Development National Center for Environmental Assessment, Research Triangle Park, NC September 30, 2015

2 Presentation Outline Regulatory context National Ambient Air Quality Standards Identifying populations at increased risk Defining factors/populations Evaluating the scientific evidence Characterizing the scientific evidence Ozone example Research opportunities 1

3 2 Research/Assessment/Management

4 Risk Assessment Dose - Response Assessment Statutory and Legal Considerations Political Considerations Public Health Considerations Risk Management Hazard Identification Exposure Assessment Risk Characterization Risk Mangement Options Economic Factors Regulatory Decisions Social Factors 3

5 Recent NRC Recommendations for Risk Assessment at EPA National Research Council (NRC) publications on risk assessment 2009: Science and Decisions the Silver Book 2011: Review of the Formaldehyde Assessment Roadmap for Revision 2013 / 2014:Critical Aspects of EPA s IRIS Assessment of Inorganic Arsenic (An Interim Report) 2014: Review of EPA s Integrated Risk Information System (IRIS) Process 4 all included suggestions for considering susceptible populations

6 National Ambient Air Quality Standards (NAAQS) Clean Air Act (CAA) requires the NAAQS for criteria air pollutants (O 3, PM, NO 2, SO 2, CO, Pb) to be reviewed every 5 years Workshop on science-policy issues Integrated Review Plan (IRP): timeline and key policy-relevant issues and scientific questions Peer-reviewed scientific studies Call for information Integrated Science Assessment (ISA): evaluation and synthesis of most policy-relevant studies Risk/Exposure Assessment (REA): quantitative assessment, as warranted, focused on key results, observations, and uncertainties Clean Air Scientific Advisory Committee (CASAC) review Public comment Policy Assessment (PA): staff analysis of policy options based on integration and interpretation of information in the ISA and REA EPA proposed decisions on standards Interagency review Agency decision making and draft proposal notice 5 Public hearings and comments on proposal Agency decision making and draft final notice Interagency review EPA final decisions on standards

7 Integrated Science Assessments (ISAs) ISAs provide the scientific basis for each NAAQS review Systematic and comprehensive review of the scientific literature Integration of health effects across scientific disciplines Concludes with a causal determination using a weight-of-evidence framework for a specific exposure duration and effect Causal relationship Likely to be a causal relationship Suggestive, but not sufficient, to infer a causal relationship Inadequate evidence No evidence of a causal relationship 6

8 Basis for Characterizing Populations Potentially At-Risk of an Air Pollutant- Induced Health Effect The primary NAAQS are intended to provide an adequate margin of safety that is requisite to protect public health. Under the NAAQS, public health protection is provided for both the population as a whole and those groups potentially at increased risk. 7 As a result, previous assessments consisted of a Public Health Impact chapter to identify those populations at greatest risk Within this chapter populations were often defined/categorized as susceptible or vulnerable The Clean Air Scientific Advisory Committee (CASAC) of EPA s Science Advisory Board recommended further evaluation of groups potentially at increased risk

9 Susceptible vs Vulnerable Definition Susceptible: Predisposed to develop a noninfectious disease Vulnerable: Capable of being hurt: susceptible to injury or disease. Susceptible: Greater likelihood of an adverse outcome given a specific exposure, in comparison with the general population. Includes both host and environmental factors (e.g., genetics, diet, physiologic state, age, gender, social, economic, and geographic attributes). Vulnerable: Periods during an individual s life when they are more susceptible to environmental exposures. Susceptible: Intrinsic (e.g., age, gender, pre-existing disease [e.g., asthma] and genetics) and extrinsic (previous exposure and nutritional status) factors. Vulnerable Population: Groups of people particularly impacted, may include children, people with disabilities, people who are chronically ill, the elderly, environmental justice populations or people living in an area prone to impacts such as flooding. Reference Merriam-Webster (2009) American Lung Association (2001) Kleeberger and Ohtsuka (2005) Resilience and Adaptation in New England (2015) Susceptible: Characteristics that contribute to increased risk of PM-related health effects (e.g., genetics, pre-existing disease, age, gender, race, socioeconomic status, healthcare availability, educational attainment, and housing characteristics). Pope and Dockery (2006) Susceptible: May refer to life stages, for example, children or the elderly, or to other segments of the population, for example, asthmatics or the immune-compromised, but are likely to be somewhat chemical-specific 8 and may not be consistently defined in all cases. IRIS Glossary (2011)

10 Defining factors that may potentially lead to increased risk Starting with the 2009 Particulate Matter (PM) ISA, EPA moved away from defining factors as either susceptible or vulnerable because it reduced the focus on the main goal of answering the question: Which individual- and population-level factors result in increased risk of an air pollutant-related health effect? All-encompassing term Sacks et al. Particulate Matter-Induced Health Effects: Who Is Susceptible? Environ Health Perspect 119: (2011). Continued evolution Populations potentially at-risk 9

11 Ozone: Air Pollution Health Effects Pyramid Mortality Hospital admissions Emergency room visits Physician office visits Reduced physical performance Medication use Respiratory symptoms Impaired lung function Sub-clinical (subtle) effects Severity of effect proportion of population affected

12 Evaluation of the Scientific Evidence Integration of evidence across disciplines Epidemiology, toxicology, controlled human exposure When possible, bringing in dosimetry, mode of action, and exposure science Focus on specific study designs: Epidemiology: stratified analyses (e.g., male vs. female, <65 versus >65, etc) Toxicological: e.g., animal models of disease and aging, genetic predisposition Controlled human exposure: e.g., underlying disease, age, genetic polymorphisms 11

13 Controlled Human Exposures Common endpoints showing O 3 -induced effects with exposures to 0.08 ppm and greater Pulmonary Function Forced Expiratory Volume in One Second (FEV 1 ) Symptoms of Breathing Discomfort Pain on deep inspiration, shortness of breath, cough Airway Hyperresponsiveness Specific - Allergens Nonspecific - Exercise, cold air, histamine Bronchioalveolar Lavage Inflammation Epithelial permeability

14 Young healthy adults 6.6 hr exposures Source: Brown et al. (2008) 24

15 Evaluation of the Scientific Evidence Identification of factors that potentially result in increased (or decreased risk) is comprised of: Intrinsic factors (i.e., biological factors) Extrinsic factors (i.e., non-biological factors) Increased dose Differential exposure 14

16 Evaluation of Variability: Disease 15 Source: ISA for ozone (2013)

17 Evaluation of Variability: Lifestage 16 Source: ISA for ozone (2013)

18 At Risk Framework some inconsistency substantial, consistent evidence insufficient quantity, quality, consistency and/or statistical power 17 Source: U.S. EPA. Integrated Science Assessment for Ozone and Related Photochemical Oxidants (Final Report). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R-10/076F, 2013.

19 18 Pre-existing Asthma Controlled human exposure studies: People with asthma at least as sensitive to healthy nonasthmatic subjects Evidence of decrements in lung function Greater inflammatory responses in people with asthma Epidemiologic studies: Limited number of studies focusing on people with and without asthma Some evidence for decreases in lung function Toxicological studies: Provide biological plausibility Example from the O 3 ISA: Adequate Evidence Animal models of asthma demonstrate pulmonary changes and inflammation due to O 3 in combination with allergic sensitization

20 Genetics Example from the Ozone ISA: Adequate Evidence Epidemiologic studies: evidence that polymorphisms in specific genes associated with anti-oxidant function (i.e., glutathione S-transferase [GST] genes) lead to O 3 -induced increases in respiratory symptoms and decreases in lung function Controlled human exposure studies: providing coherence for the same effects observed in epidemiologic studies Toxicological studies: mice with KOs of genes in the GST family had O 3 -induced inflammation and airways hyperreactivity providing biological plausibility 19

21 20 Socioeconomic Status (SES) Epidemiologic studies: Example from the O 3 ISA: Suggestive Evidence Respiratory-related hospital admission/ed visit studies report generally increased associations by measures of low SES Short-term O 3 exposure and mortality studies reported inconsistent evidence for differences by SES Inconsistent evidence for differences by SES on reproductive outcomes Interpretation of evidence complicated by: Variety of metrics used to represent SES Classification of SES in studies conducted outside the U.S. compared to in the U.S. Controlled human exposure studies: Some evidence for differences in lung function by SES

22 Summary of Evidence for Potential Increased Risk of O 3 -Induced Health Effects 21 Evidence Classification Potential At Risk Factor Adequate Evidence Genetic factors (Section 8.1) Asthma (Section 8.2.2) Children (Section ) Older Adults (Section ) Diet (Section 8.4.1) Outdoor workers (Section 8.4.4) Suggestive Evidence Sex (Sections 8.3.2) Socioeconomic Status (SES) (Section 8.3.3) Obesity (Section 8.4.2) Inadequate Evidence Influenza/Infection (Section 8.2.1) COPD (Section 8.2.3) CVD (Section 8.2.4) Diabetes (Section 8.2.5) Hyperthyroidism (Section 8.2.6) Race/ethnicity (Section 8.3.4) Smoking (Section 8.4.3) Air conditioning use (Section 8.4.5) Evidence of No Effect --- Source: U.S. EPA. Integrated Science Assessment for Ozone and Related Photochemical Oxidants (Final Report). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R-10/076F, 2013.

23 Evidence-based approach o Informing the Decision-Making Process Reduces speculation Clear communication of scientific evidence o Directly informs additional qualitative and quantitative analyses Data availability Workshop on science-policy issues Peer-reviewed scientific studies Call for information Integrated Review Plan (IRP): timeline and key policy-relevant issues and scientific questions Integrated Science Assessment (ISA): evaluation and synthesis of most policy-relevant studies Risk/Exposure Assessment (REA): quantitative assessment, as warranted, focused on key results, observations, and uncertainties Clean Air Scientific Advisory Committee (CASAC) review Public comment Policy Assessment (PA): staff analysis of policy options based on integration and interpretation of information in the ISA and REA EPA proposed decisions on standards Interagency review Agency decision making and draft proposal notice 22 Public hearings and comments on proposal Agency decision making and draft final notice Interagency review EPA final decisions on standards

24 Normal Subjects demonstrate Intersubject variability in responses to ozone FEV 1 %Change ppb 0% 60 ppb 16% (n=5) 70 ppb 19% (n=6) 80 ppb 29% (n=9) 87 ppb 42% (n=13) -30 Number of Individuals (16 F, 15 M; age 18-25) Source: Modified from Schelegle et al. (2009)

25 Research Directions Interindividual variability is evident, including among normal individuals What research approaches might help us understand the biological basis for this variability? Epigenetics Others 24

26 Epigenetics-Risk Assessment *Inform understanding of biological mechanisms and mode of action of contaminant-disease relationships *Include epigenetic modification in doseresponse estimates between contaminant and disease *Potential to be used as both biomarkers of exposure and effect *Predict inter-individual differences in outcomes responders and non-responders to exposure 25 Courtesy of Rebecca Fry

27 A B C D E Courtesy of Shaun McCullough, EPA/NHEERL

28 Ozone Model Figure 5. Seed and Soil Model for the Epigenetic Basis of Inter-Individual Variability in Exposure Responses. Toxicant-induced cellular signals (the seed ) are transduced to the nucleus where they interact with the chromatin landscape to alter the expression of toxicant-responsive genes. The state of chromatin in a target tissue prior to toxicant exposure (the soil ) varies between individuals. These intrinsic variations in the soil, as reflected by specific histone modifications or DNA methylation states (i.e. 5-hmC), induce expression of exposure-responsive genes to different degrees as an outcome of the seed and soil interaction. Our findings suggest that this model may apply to specific chromatin modifications at the promoters of some, but not all genes that are induced in response to an individual toxicant. Courtesy of Shaun McCullough, EPA/NHEERL

29 Conclusions Use of At Risk Framework provides clear communication of scientific evidence Unique At Risk factors will likely exist for specific pollutants / chemicals An understanding of the factors influencing interindividual variability is relevant to regulatory decision-making Research opportunities exist to further knowledge of intrinsic and extrinsic factors affecting variability in response to pollutant exposure 28

30 Acknowledgements Reeder Sams (EPA/NCEA) Jason Sacks (EPA/NCEA) James Brown (EPA/NCEA) Shaun McCullough (EPA/NHEERL) Rebecca Fry (UNC) EPA/NCEA staff 29